Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway

Abstract

Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco, has been implicated as playing a role in carcinogenesis. Our previous study showed that passive cigarette smoking promoted inflammation-associated colonic adenoma formation in mice, and 5-lipoxygenase (5-LOX) plays an important role in this process. In the present study, we aimed to investigate whether nicotine could stimulate colon cancer cell proliferation and tumor growth in nude mice xenograft model and the possible mechanisms involved. Results showed that nicotine stimulated SW1116 colon cancer cell proliferation in a dose-dependent manner. Epidermal growth factor receptor (EGFR) and c-Src phosphorylation levels together with protein expression of 5-LOX were also significantly enhanced in this proliferation process. Inhibitors of EGFR and c-Src alleviated the actions of nicotine on cell proliferation and 5-LOX protein expression. Combination of both agents produced additive effect. In contrast, 5-LOX inhibitor had no direct effect on the phosphorylation levels of EGFR and c-Src and yet inhibited cell proliferation. In the colon cancer xenograft model, nicotine also significantly enhanced tumor growth. This acceleration of tumor growth corresponded well with increased vascularization and its proangiogenic factors. Inhibitors of EGFR, c-Src, and 5-LOX all significantly impeded the tumor growth induced by nicotine. Together, nicotine can promote colonic tumorigenesis both in vitro and in vivo. Activation of the phosphorylated form of EGFR and c-Src followed by an increased 5-LOX expression are the prime pathogenic mechanisms in the tumorigenic process in the colon.

Cytochrome P450 Epoxygenase CYP2J2 G-50T Polymorphism is an Independent Genetic Prognostic Risk Factor and Interacts with Smoking Cessation After Index Premature Myocardial Infarction

“…Patients carrying T allele at promoter region of CYP2J2 gene thus had lower median value of 14,15 EETs concentrations, which might protect their coronary vasculatures. In addition, smoking could alter the metabolites of arachidonic acid (Ye et al, 2004). This effect was observed, in our study, more significantly among CYP2J2 G-50T polymorphism carriers whom probably were more prone to the oxidative stress damage due to their impaired EETs functions.…”

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients

“…This methodology could led to a selection bias excluding deceased patients possibly with a worst prognosis. This point could represent the reason of the longer TTP and OS observed in our analysis when compared with that observed with the same cancer population in published clinical trials (9). On the contrary the observed response rate in the population of smokers vs. nonsmokers is reasonably reliable.…”

“…Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine, was able to stimulate the proliferation of SW1116 colon cancer cell line enhancing NF-κB DNA binding activity (7). Moreover, nicotine, the major alcaloid in tobacco, increases the oxidative stress of colon cancer cells, leading to the activation of NF-κB, a redox-sensitive trascription factor (8) and promotes colon cancer cell proliferation and tumor growth in a dose-dependent manner, increasing EGFR phosphorylation levels (9).…”

Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer

“…Tumor cell proliferation, angiogenesis, and local and distant cell migration are hallmarks of solid tumors. Our recent studies show that nicotine induces proliferation of human adenocarcinoma cells via a cyclooxygenase (COX)/lipoxygenase -dependent pathway to metabolize fatty acids into eicosanoids (4,5). The effects of COX-2 inhibitors on treatment and chemoprevention of gastric cancer have been widely reported (6,7).…”